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Cited by 99Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice

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Liu, De-shan, Pan, Xiao-dong, Zhang, Jing, Shen, Hui, Collins, Nicole C, Cole, Arron M, Koster, Kevin P, Ben Aissa, Manel +6 more·2015·Molecular Neurodegeneration
DOI 10.1186/s13024-015-0002-2PMC PMC4391134
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Abstract

BACKGROUND: Alzheimer's disease (AD) causes progressive loss of memory and cognition, exacerbated by APOE4, the greatest genetic risk factor for AD. One proposed mechanism for apolipoprotein E (apoE) effects on cognition is via NMDAR-dependent signaling. APOE genotype-specific effects on this pathway were dissected using EFAD-transgenic (Tg) mice (5xFAD mice, that over-express human amyloid-beta (Aβ) via 5 familial-AD (FAD) mutations, and express human apoE), and 5xFAD/APOE-knockout (KO) mice. Previous data from EFAD-Tg mice demonstrate age-dependent (2-6 months), apoE-specific effects on the development of Aβ pathology. This study tests the hypothesis that apoE4 impairs cognition via modulation of NMDAR-dependent signaling, specifically via a loss of function by comparison of E4FAD mice with 5xFAD/APOE-KO mice, E3FAD and E2FAD mice. RESULTS: Using female E2FAD, E3FAD, E4FAD and 5xFAD/APOE-KO mice aged 2-, 4-, and 6-months, the Y-maze and Morris water maze behavioral tests were combined with synaptic protein levels as markers of synaptic viability. The results demonstrate a greater age-induced deficit in cognition and reduction in PSD95, drebrin and NMDAR subunits in the E4FAD and 5xFAD/APOE-KO mice compared with E2FAD and E3FAD mice, consistent with an apoE4 loss of function. Interestingly, for NMDAR-mediated signaling, the levels of p-CaMK-II followed this same apoE-specific pattern as cognition, while the levels of p-CREB and BDNF demonstrate an apoE4 toxic gain of function: E2FAD > E3FAD > 5xFAD/APOE-KO > E4FAD. CONCLUSION: These findings suggest that compared with E2FAD and E3FAD, E4FAD and 5xFAD/APOE-KO mice exhibit enhanced age-induced reductions in cognition and key synaptic proteins via down-regulation of an NMDAR signaling pathway, consistent with an apoE4 loss of function. However, levels of p-CREB and BDNF, signaling factors common to multiple pathways, suggest a gain of toxic function. Publications in this field present contradictory results as to whether APOE4 imparts a loss or gain of function. As with the results reported herein, the overall effect of APOE4 on a given CNS-specific measure will be the product of multiple overlapping mechanisms. Thus, caution remains critical in determining whether APOE gene inactivation or therapies that correct the loss of positive function related to apoE4, are the appropriate therapeutic response.

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  • APOE4 was previously shown to accelerate AD progression in humans and in mouse models.

    “The APOE4 allele is a major genetic risk factor for late-onset AD and was previously shown to accelerate AD progression in humans and in mouse models 6-11 .”

    From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [11]

    The Introduction reports earlier onset of cognitive deficits in human APOE4 carriers, but says evidence for a faster rate of cognitive decline is conflicting. The Discussion reports a more rapid early decline in spatial recognition memory in E4FAD mice. Thus, the source supports the mouse finding and earlier human onset, but not an unqualified claim that APOE4 accelerates AD progression in humans. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The APOE4 allele is a major genetic risk factor for late-onset Alzheimer's disease.

    “The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD).”

    From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [11]

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Authors
Liu, D.-S., Pan, X.-D., Zhang, J., Shen, H., Collins, N. C., Cole, A. M., Koster, K. P., Ben Aissa, M., Dai, X.-M., Zhou, M., Tai, L. M., Zhu, Y.-G., LaDu, M. J., & Chen, X.-C.
Affiliations
  • Fujian Medical University (CN)
  • University of Illinois Chicago (US)
Corresponding author
LaDu, Mary Jo
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2015-03-05
Volume
10
Issue
1
Pages
7-7
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-015-0002-2
PMC
PMC4391134
OpenAlex
W2144850899
Cited by
99
References
134
Citations by year
2026: 4 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 8 · 2018: 5 · 2017: 15 · 2016: 10
FWCI
7.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81200991, 81171216, 81071007)
  • National Institutes of Health
  • University of Illinois at Urbana-Champaign
  • National Institute on Aging (P01AG030128, R21AG048498)
  • National Center for Research Resources (UL1RR029879)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, NMDA receptor signaling, cognitive decline, 5xFAD mice, amyloid-beta, synaptic proteins, PSD-95, drebrin, CaMKII, CREB, brain-derived neurotrophic factor, loss of function, gain of toxic function, APOE isoforms, apolipoprotein E deficiency
MeSH terms
Aging, Alzheimer Disease, Animals, Cognition, Memory, Mutation, Signal Transduction, Down-Regulation, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Mice, Knockout, Apolipoprotein E4

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